{"gene":"ABCC9","run_date":"2026-06-09T22:02:36","timeline":{"discoveries":[{"year":2004,"finding":"Missense and frameshift mutations in ABCC9 (encoding SUR2A) map to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A, causing aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle and translating into abnormal KATP channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction.","method":"Genomic DNA scanning, functional characterization of mutant SUR2A proteins (ATPase activity assays, electrophysiology)","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — in vitro ATPase assays and electrophysiology with mutagenesis in a single rigorous study","pmids":["15034580"],"is_preprint":false},{"year":2008,"finding":"SUR2A contains ATPase activity harbored within NBD2 and, to a lesser degree, NBD1. Heterodomain NBD1/NBD2 interaction (demonstrated by nanoscale protein topography, circular dichroism, atomic force and transmission electron microscopy) produces conformational rearrangements and enhances intrinsic ATPase activity. Mutation of the predicted catalytic base residue D834E in NBD1 altered NBD1 ATPase activity and disrupted potentiation of catalytic behavior in the NBD1/NBD2 interactome.","method":"Purified recombinant SUR2A NBD1/NBD2 domains; dynamic light scattering; atomic force microscopy; transmission electron microscopy; circular dichroism; ATPase activity assays; site-directed mutagenesis (D834E)","journal":"Journal of proteome research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal structural and biochemical methods plus mutagenesis in one study","pmids":["18311911"],"is_preprint":false},{"year":2012,"finding":"Dominant missense mutations in ABCC9 causing Cantú syndrome reduce ATP-mediated inhibition of the KATP channel, resulting in channel opening (gain-of-function). All mutations altered amino acids in or close to the transmembrane domains of SUR2.","method":"Family-based exome sequencing; electrophysiological measurements of mutant channels","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — electrophysiology confirmed in 14/16 individuals; replicated by independent group (PMID:22608503)","pmids":["22610116","22608503"],"is_preprint":false},{"year":2012,"finding":"Cantú syndrome mutations in ABCC9 are missense and affect a mutation hotspot at Arg1154 within the second type 1 transmembrane region of SUR2, consistent with an activating (gain-of-function) mechanism for the KATP channel.","method":"Exome sequencing of proband-parent trios and unrelated cases; Sanger sequencing validation","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 3 / Strong — sequencing only without direct functional assay in this paper, but independently replicated","pmids":["22608503"],"is_preprint":false},{"year":2012,"finding":"CpG methylation of the ABCC9 (SUR2) promoter regulates its expression in cardiomyocytes. Bisulfite sequencing showed 57.6% CpG methylation in the SUR2 promoter in HL-1 cells (vs. 0.14% for SUR1), and treatment with 5-aza-2'-deoxycytidine increased both unmethylated CpG fraction and SUR2 mRNA expression.","method":"Bisulfite sequencing of genomic DNA; 5-aza-2'-deoxycytidine treatment; quantitative mRNA expression analysis in HL-1 cardiomyocytes","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal methods (bisulfite sequencing + pharmacological demethylation) in single lab; caveats acknowledged about non-methylation effects of Aza-dC","pmids":["22844491"],"is_preprint":false},{"year":2013,"finding":"The V734I mutation in ABCC9 (SUR2B) reduces sensitivity of Kir6.2/SUR2B channels to MgATP inhibition and reduces MgNDP (MgADP, MgGDP, MgUDP) activation, specifically in vascular (Kir6.2/SUR2B) but not cardiac (Kir6.2/SUR2A) or Kir6.1/SUR2B channel combinations, implicating impaired vascular KATP channel response to intracellular nucleotides in susceptibility to coronary spasm and myocardial infarction.","method":"Patch-clamp electrophysiology (inside-out patches) of mutant channels coexpressed in Xenopus oocytes or HEK cells; splice variant-specific analysis of SUR2A vs SUR2B","journal":"International journal of cardiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous inside-out patch-clamp with multiple nucleotide conditions and multiple channel subunit combinations, single lab","pmids":["23739550"],"is_preprint":false},{"year":2014,"finding":"ABCC9 mutations (V734I and S1402C) cause gain-of-function of IK-ATP: V734I yielded a Mg-ATP IC50 5-fold that of wild-type; S1402C shifted ATP IC50 from 8.5 ± 2 mM to 13.4 ± 5 µM. These gain-of-function variants are associated with Brugada and early repolarization syndromes.","method":"Whole-cell and inside-out patch-clamp of mutant channels expressed in TSA201 cells; direct sequencing","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous electrophysiology but single lab; small patient cohort","pmids":["24439875"],"is_preprint":false},{"year":2014,"finding":"Abcc9 is required for the neonatal heart's transition from glycolytic to oxidative (mitochondrial) metabolism. Abcc9 knockout (exon 5 deletion) cardiomyocytes showed mitochondria unresponsive to the KATP agonist diazoxide, rapid mitochondrial membrane potential collapse under oxidative stress, reduced fatty acid oxidation, reduced oxygen consumption, and morphologically immature mitochondria with reduced cross-sectional area and intermitochondrial contacts.","method":"Mouse knockout model (exon 5 deletion); mitochondrial membrane potential assays; diazoxide stimulation; fatty acid oxidation assays; oxygen consumption measurements; electron microscopy","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional readouts in KO mouse model; single lab","pmids":["24648545"],"is_preprint":false},{"year":2015,"finding":"Three Cantú syndrome ABCC9 mutations (P432L/P429L, A478V/A475V, C1043Y/C1039Y in human/rat SUR2A) all cause gain-of-function via at least two distinct mechanisms: P429L and A475V mutations enhance MgADP activation without altering ATP inhibition sensitivity; C1039Y mutation decreases ATP inhibition sensitivity and glibenclamide sensitivity without altering MgADP activation.","method":"Macroscopic 86Rb+ efflux assays; inside-out patch-clamp electrophysiology measuring ATP inhibition and MgADP activation; channels coexpressed with Kir6.2 in Xenopus oocytes","journal":"The Journal of general physiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — two orthogonal functional assays (Rb+ efflux + patch-clamp) with multiple mutants, single lab","pmids":["26621776"],"is_preprint":false},{"year":2019,"finding":"A homozygous splice-site mutation in ABCC9 (c.1320+1 G>A) causes in-frame deletion of exon 8, resulting in non-functional SUR2-containing KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice and reduced activity, cardiac dysfunction, and ventricular enlargement in zebrafish, defining the ABCC9-related Intellectual disability Myopathy Syndrome (AIMS).","method":"Recombinant channel expression and functional assays; mouse phenotyping; zebrafish phenotyping; patient exome sequencing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — recombinant functional assay plus two animal model phenotyping studies, single coordinated study","pmids":["31575858"],"is_preprint":false},{"year":2019,"finding":"Four rare ABCC9 missense variants (A355S, M941V, H1305Y, K1379Q) identified in sudden unexpected natural death cases all produce gain-of-function phenotypes when expressed as SUR2A with Kir6.2 in HEK-293 cells: A355S and M941V increase overall patch current; M941V, H1305Y, and K1379Q reduce sensitivity to inhibitory cytosolic ATP. None altered unitary channel current or surface expression (biotinylation assays), indicating enhanced open-state probability.","method":"Patch-clamp electrophysiology; surface biotinylation assays in HEK-293 cells expressing human SUR2A + Kir6.2","journal":"Forensic science international","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous patch-clamp plus biochemical assay but single lab, no replication","pmids":["30878466"],"is_preprint":false},{"year":2022,"finding":"KCNJ8/ABCC9-containing KATP channel cell-autonomously regulates brain vascular smooth muscle cell (VSMC) differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Genetic/chemical inhibition or activation of KATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar VSMC differentiation. Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and impaired neuronal-evoked vasodilation.","method":"Mouse knockout; zebrafish genetic models; cell culture; pharmacological KATP channel inhibition/activation; intracellular Ca2+ imaging; neurovascular coupling measurements","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple model organisms (mouse, zebrafish, cell culture) with pharmacological and genetic manipulation plus mechanistic Ca2+ imaging","pmids":["35588738"],"is_preprint":false},{"year":2022,"finding":"A heterozygous ABCC9 in-frame deletion variant (indel1055; p.Leu1055_Glu1058delinsPro) in SUR2A causes gain-of-function with increased IC50 for ATP inhibition, as demonstrated by inside-out patch-clamp of channels formed by Kir6.2 and mutant SUR2A in Cosm6 cells. A second variant p.Ile416Thr did not differ functionally from wild-type.","method":"Inside-out patch-clamp electrophysiology of mutant SUR2A + Kir6.2 in Cosm6 cells","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous patch-clamp but single variant in single lab, no replication","pmids":["36336713"],"is_preprint":false},{"year":2024,"finding":"A novel heterozygous ABCC9 variant (p.Gly814Trp) in SUR2B causes gain-of-function KATP channel activity: cells expressing hKir6.1/hSUR2B-Gly814Trp showed hyperpolarized membrane potential, and inside-out patch-clamp demonstrated decreased sensitivity to ATP inhibition. The location of this variant in the signature motif of NBD1 reveals an unrecognized functional role of the first glycine in the ABC protein NBD signature motif.","method":"Stable cell expression of hKir6.1 + hSUR2B mutant; membrane potential measurements; inside-out patch-clamp electrophysiology","journal":"American journal of medical genetics. Part A","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — patch-clamp with membrane potential readout, single lab, single variant","pmids":["39031464"],"is_preprint":false},{"year":2025,"finding":"ABCC9 knockdown in isoproterenol-treated AC16 cardiomyocytes attenuates myocardial hypertrophy and reduces cardiomyocyte apoptosis and oxidative stress by inhibiting the PI3K/AKT signaling pathway and improving mitochondrial membrane potential. The protective effects were abolished by PI3K/AKT activator 740Y-P, placing ABCC9 upstream of PI3K/AKT in this pathway.","method":"siRNA knockdown in AC16 cardiomyocytes; western blot for PI3K/AKT pathway components; mitochondrial membrane potential assay; flow cytometry for ROS and apoptosis; pharmacological rescue with 740Y-P","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — epistasis via pharmacological rescue plus multiple readouts, single lab, no replication","pmids":["41347799"],"is_preprint":false},{"year":2020,"finding":"TRIM11 promotes ABCC9 expression in nasopharyngeal carcinoma by ubiquitin-mediated (p62-selective autophagic) degradation of Daple, which upregulates β-catenin, which directly binds the ABCC9 promoter to induce its transcription, thereby enhancing multidrug resistance.","method":"qRT-PCR; Co-IP; ubiquitination assays; promoter binding assays; in vitro and in vivo cisplatin resistance models","journal":"Oncogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — multiple mechanistic assays (Co-IP, promoter binding, in vivo) but single lab; ABCC9 is downstream effector in this pathway","pmids":["32382014"],"is_preprint":false}],"current_model":"ABCC9 encodes SUR2, the regulatory subunit of heterooctameric KATP channels (with Kir6.x pore-forming subunits); SUR2 harbors ATPase activity in its asymmetric NBD1/NBD2 domains whose heterodomain interaction optimizes catalytic output, and catalytically driven conformational changes gate the Kir6 channel pore—gain-of-function mutations (reducing ATP inhibition or enhancing MgADP activation) cause Cantú syndrome and arrhythmia susceptibility, while loss-of-function mutations cause dilated cardiomyopathy, intellectual disability/myopathy syndrome (AIMS), and neonatal metabolic failure; the KATP channel additionally regulates brain VSMC differentiation via Ca2+ oscillation, and ABCC9 expression is regulated at the transcriptional level by CpG methylation and by the TRIM11/Daple/β-catenin axis."},"narrative":{"mechanistic_narrative":"ABCC9 encodes SUR2, the regulatory subunit that assembles with Kir6.x pore-forming subunits to form ATP-sensitive potassium (KATP) channels coupling cellular metabolic state to membrane excitability [PMID:15034580, PMID:22610116, PMID:22608503]. SUR2 harbors intrinsic ATPase activity concentrated in NBD2 and, to a lesser degree, NBD1, whose heterodomain NBD1/NBD2 interaction drives conformational rearrangements that potentiate catalysis and translate nucleotide binding into pore regulation [PMID:18311911]. This catalytic cycle decodes intracellular nucleotide signals: ATP binding inhibits the channel while MgADP/MgNDP binding activates it, and disease mutations distort this balance through at least two distinct routes—reduced ATP inhibition or enhanced MgADP activation—both yielding gain-of-function channel opening [PMID:23739550, PMID:26621776, PMID:36336713]. Gain-of-function ABCC9 variants cause Cantú syndrome [PMID:22610116, PMID:22608503] and confer susceptibility to arrhythmia, Brugada/early repolarization, and sudden death [PMID:24439875, PMID:30878466], whereas loss-of-function from a homozygous splice variant defines ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) with cardiac dysfunction in mouse and zebrafish models [PMID:31575858]. Beyond excitability, ABCC9 is required for the neonatal cardiac transition to oxidative mitochondrial metabolism [PMID:24648545], and the KCNJ8/ABCC9 channel cell-autonomously regulates brain vascular smooth muscle differentiation through Ca2+ oscillation [PMID:35588738]. ABCC9 transcription is controlled by CpG methylation of its promoter [PMID:22844491] and by a TRIM11/Daple/β-catenin axis that drives multidrug resistance in nasopharyngeal carcinoma [PMID:32382014].","teleology":[{"year":2004,"claim":"Established that ABCC9 disease mutations cluster near the SUR2A catalytic ATPase pocket and act by distorting the intrinsic ATP hydrolytic cycle, defining defective catalysis-mediated pore regulation as a disease mechanism.","evidence":"Genomic DNA scanning plus ATPase and electrophysiology assays of mutant SUR2A","pmids":["15034580"],"confidence":"High","gaps":["Did not resolve the structural basis of how catalysis gates the Kir6 pore","Specific clinical phenotype-mutation correlations not yet established"]},{"year":2008,"claim":"Localized SUR2A ATPase activity to the nucleotide-binding domains and showed the asymmetric NBD1/NBD2 heterodomain interaction potentiates catalysis, explaining how nucleotide sensing is mechanically organized.","evidence":"Purified recombinant NBD1/NBD2 domains analyzed by AFM, TEM, circular dichroism, ATPase assays and D834E mutagenesis","pmids":["18311911"],"confidence":"High","gaps":["Domain studies done in isolation, not in intact assembled channel","Link from NBD conformational change to pore gating inferred, not directly visualized"]},{"year":2012,"claim":"Identified ABCC9 gain-of-function mutations reducing ATP inhibition as the cause of Cantú syndrome, establishing a human disease driven by excess KATP channel opening.","evidence":"Family-based and trio exome sequencing with electrophysiology of mutant channels; independent replication","pmids":["22610116","22608503"],"confidence":"High","gaps":["Tissue-specific contributions of different SUR2 splice variants not resolved","Mechanism by which transmembrane-domain mutations alter ATP sensitivity not structurally defined"]},{"year":2013,"claim":"Demonstrated splice-variant- and tissue-specificity of ABCC9 channel dysfunction, showing the V734I variant selectively impairs vascular (SUR2B) nucleotide responses linked to coronary spasm.","evidence":"Inside-out patch-clamp of mutant channels across SUR2A/SUR2B/Kir6.x combinations in oocytes and HEK cells","pmids":["23739550"],"confidence":"High","gaps":["In vivo vascular phenotype of the variant not tested","Did not address why the same variant is benign in cardiac channels mechanistically"]},{"year":2014,"claim":"Broadened the arrhythmia spectrum by showing ABCC9 gain-of-function variants underlie Brugada and early repolarization syndromes via increased IK-ATP.","evidence":"Whole-cell and inside-out patch-clamp of mutant channels in TSA201 cells with sequencing","pmids":["24439875"],"confidence":"Medium","gaps":["Single lab, small patient cohort","Causality at the organismal/clinical level not established"]},{"year":2014,"claim":"Revealed a metabolic role beyond excitability, showing Abcc9 is required for the neonatal heart's switch from glycolytic to oxidative mitochondrial metabolism.","evidence":"Abcc9 knockout mouse with mitochondrial membrane potential, fatty acid oxidation, oxygen consumption assays, diazoxide stimulation and electron microscopy","pmids":["24648545"],"confidence":"High","gaps":["Molecular link between sarcolemmal KATP channel function and mitochondrial maturation unresolved","Whether the effect is channel-dependent or independent not dissected"]},{"year":2015,"claim":"Resolved that Cantú gain-of-function arises through at least two mechanistically distinct routes—enhanced MgADP activation versus decreased ATP inhibition—clarifying the molecular heterogeneity of a single syndrome.","evidence":"86Rb+ efflux and inside-out patch-clamp of multiple Cantú mutants coexpressed with Kir6.2 in oocytes","pmids":["26621776"],"confidence":"High","gaps":["Whether the two mechanisms produce distinct clinical severity not addressed","Structural correlates of each mechanism not defined"]},{"year":2019,"claim":"Defined the loss-of-function end of the ABCC9 spectrum, showing a splice variant producing non-functional channels causes the AIMS syndrome with conserved phenotypes across species.","evidence":"Recombinant channel assays plus mouse and zebrafish phenotyping with patient exome sequencing","pmids":["31575858"],"confidence":"High","gaps":["Mechanism linking SUR2 loss to intellectual disability/myopathy not detailed","Cell types driving each phenotypic feature not isolated"]},{"year":2019,"claim":"Connected rare ABCC9 variants to sudden unexpected death by showing they enhance open-state probability without altering unitary current or surface expression.","evidence":"Patch-clamp and surface biotinylation of human SUR2A + Kir6.2 in HEK-293 cells","pmids":["30878466"],"confidence":"Medium","gaps":["Single lab, no replication","Direct causal contribution to death events not established"]},{"year":2022,"claim":"Uncovered a developmental role in which the KCNJ8/ABCC9 channel cell-autonomously controls brain vascular smooth muscle differentiation via Ca2+ oscillation, linking the channel to neurovascular coupling.","evidence":"Mouse and zebrafish genetics, cell culture, pharmacology, Ca2+ imaging and neurovascular coupling measurements","pmids":["35588738"],"confidence":"High","gaps":["Why this regulation is brain-selective not fully explained","Connection to Cantú vascular phenotypes not directly tested"]},{"year":2022,"claim":"Added an in-frame deletion gain-of-function variant with increased ATP IC50, extending the catalogue of ATP-inhibition-impairing mutations.","evidence":"Inside-out patch-clamp of mutant SUR2A + Kir6.2 in Cosm6 cells","pmids":["36336713"],"confidence":"Medium","gaps":["Single variant, single lab, no replication","Clinical phenotype not functionally tied to the variant"]},{"year":2024,"claim":"Assigned a functional role to the first glycine of the ABC NBD signature motif by showing a SUR2B variant there causes gain-of-function with reduced ATP sensitivity.","evidence":"Stable hKir6.1 + hSUR2B mutant expression with membrane potential and inside-out patch-clamp","pmids":["39031464"],"confidence":"Medium","gaps":["Single variant, single lab","Structural mechanism by which the signature-motif glycine controls ATP gating not resolved"]},{"year":2025,"claim":"Placed ABCC9 upstream of PI3K/AKT signaling in cardiomyocyte hypertrophy, showing knockdown reduces apoptosis and oxidative stress dependent on this pathway.","evidence":"siRNA knockdown in AC16 cardiomyocytes with western blot, mitochondrial and ROS/apoptosis assays and pharmacological rescue with 740Y-P","pmids":["41347799"],"confidence":"Medium","gaps":["Single lab, no replication","Whether the effect requires channel activity versus a non-channel role unclear","In vivo relevance not tested"]},{"year":2020,"claim":"Identified a transcriptional regulatory axis in which TRIM11/Daple/β-catenin drives ABCC9 expression to confer multidrug resistance in nasopharyngeal carcinoma.","evidence":"qRT-PCR, Co-IP, ubiquitination and promoter binding assays with in vitro and in vivo cisplatin resistance models","pmids":["32382014"],"confidence":"Medium","gaps":["ABCC9 as downstream effector; direct drug-efflux role not demonstrated here","Single lab; generality across cancers not tested"]},{"year":null,"claim":"How catalytically driven NBD conformational changes are mechanically transmitted to gate the Kir6 pore in the assembled channel, and how the same molecule's metabolic and developmental roles relate to its channel function, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of mutation-to-gating coupling in intact octamer","Channel-dependent vs channel-independent contributions to metabolic/developmental phenotypes undissected","Tissue-specific splice-variant roles incompletely mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[2,5,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,5]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,8]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[2,5,8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,9,15]}],"complexes":["KATP channel (SUR2/Kir6.x)"],"partners":["KCNJ8","KIR6.2","KIR6.1","TRIM11","DAPLE","CTNNB1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O60706","full_name":"ATP-binding cassette sub-family C member 9","aliases":["Sulfonylurea receptor 2"],"length_aa":1549,"mass_kda":174.2,"function":"Subunit of ATP-sensitive potassium channels (KATP). Can form cardiac and smooth muscle-type KATP channels with KCNJ11. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (PubMed:9831708). Can form a sulfonylurea-sensitive but ATP-insensitive potassium channel with KCNJ8 (By similarity)","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/O60706/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABCC9","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABCC9","total_profiled":1310},"omim":[{"mim_id":"619719","title":"INTELLECTUAL DISABILITY AND MYOPATHY SYNDROME; IDMYS","url":"https://www.omim.org/entry/619719"},{"mim_id":"614050","title":"ATRIAL FIBRILLATION, FAMILIAL, 12; ATFB12","url":"https://www.omim.org/entry/614050"},{"mim_id":"608583","title":"ATRIAL FIBRILLATION, FAMILIAL, 1; ATFB1","url":"https://www.omim.org/entry/608583"},{"mim_id":"608569","title":"CARDIOMYOPATHY, DILATED, 1O; CMD1O","url":"https://www.omim.org/entry/608569"},{"mim_id":"608089","title":"ENDOMETRIAL CANCER","url":"https://www.omim.org/entry/608089"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABCC9"},"hgnc":{"alias_symbol":["SUR2","CMD1O"],"prev_symbol":[]},"alphafold":{"accession":"O60706","domains":[{"cath_id":"-","chopping":"11-214","consensus_level":"high","plddt":86.2299,"start":11,"end":214},{"cath_id":"3.40.50.300","chopping":"689-733_751-926","consensus_level":"high","plddt":82.4456,"start":689,"end":926}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O60706","model_url":"https://alphafold.ebi.ac.uk/files/AF-O60706-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O60706-F1-predicted_aligned_error_v6.png","plddt_mean":81.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABCC9","jax_strain_url":"https://www.jax.org/strain/search?query=ABCC9"},"sequence":{"accession":"O60706","fasta_url":"https://rest.uniprot.org/uniprotkb/O60706.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O60706/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O60706"}},"corpus_meta":[{"pmid":"15034580","id":"PMC_15034580","title":"ABCC9 mutations identified in human dilated cardiomyopathy disrupt catalytic KATP channel gating.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/15034580","citation_count":290,"is_preprint":false},{"pmid":"22610116","id":"PMC_22610116","title":"Dominant missense mutations in ABCC9 cause Cantú syndrome.","date":"2012","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22610116","citation_count":162,"is_preprint":false},{"pmid":"22608503","id":"PMC_22608503","title":"Cantú syndrome is caused by mutations in ABCC9.","date":"2012","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22608503","citation_count":133,"is_preprint":false},{"pmid":"24439875","id":"PMC_24439875","title":"ABCC9 is a novel Brugada and early repolarization syndrome susceptibility gene.","date":"2014","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/24439875","citation_count":105,"is_preprint":false},{"pmid":"24770881","id":"PMC_24770881","title":"ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology.","date":"2014","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/24770881","citation_count":77,"is_preprint":false},{"pmid":"32382014","id":"PMC_32382014","title":"TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple.","date":"2020","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/32382014","citation_count":74,"is_preprint":false},{"pmid":"25470345","id":"PMC_25470345","title":"Reassessment of risk genotypes (GRN, TMEM106B, and ABCC9 variants) associated with hippocampal sclerosis of aging pathology.","date":"2015","source":"Journal of neuropathology and experimental 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Case reports","url":"https://pubmed.ncbi.nlm.nih.gov/40923965","citation_count":0,"is_preprint":false},{"pmid":"39344622","id":"PMC_39344622","title":"[Clinical characteristics and genetic analysis of a child with Cantú syndrome due to variant of ABCC9 gene].","date":"2024","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39344622","citation_count":0,"is_preprint":false},{"pmid":"37239348","id":"PMC_37239348","title":"An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37239348","citation_count":0,"is_preprint":false},{"pmid":"39031464","id":"PMC_39031464","title":"A novel ABCC9 variant in a Greek family with Cantu syndrome affecting multiple generations highlights the functional role of the SUR2B NBD1.","date":"2024","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/39031464","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":19365,"output_tokens":4355,"usd":0.06171,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12366,"output_tokens":4545,"usd":0.087727,"stage2_stop_reason":"end_turn"},"total_usd":0.149437,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"Missense and frameshift mutations in ABCC9 (encoding SUR2A) map to evolutionarily conserved domains adjacent to the catalytic ATPase pocket within SUR2A, causing aberrant redistribution of conformations in the intrinsic ATP hydrolytic cycle and translating into abnormal KATP channel phenotypes with compromised metabolic signal decoding. Defective catalysis-mediated pore regulation is thus a mechanism for channel dysfunction.\",\n      \"method\": \"Genomic DNA scanning, functional characterization of mutant SUR2A proteins (ATPase activity assays, electrophysiology)\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro ATPase assays and electrophysiology with mutagenesis in a single rigorous study\",\n      \"pmids\": [\"15034580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SUR2A contains ATPase activity harbored within NBD2 and, to a lesser degree, NBD1. Heterodomain NBD1/NBD2 interaction (demonstrated by nanoscale protein topography, circular dichroism, atomic force and transmission electron microscopy) produces conformational rearrangements and enhances intrinsic ATPase activity. Mutation of the predicted catalytic base residue D834E in NBD1 altered NBD1 ATPase activity and disrupted potentiation of catalytic behavior in the NBD1/NBD2 interactome.\",\n      \"method\": \"Purified recombinant SUR2A NBD1/NBD2 domains; dynamic light scattering; atomic force microscopy; transmission electron microscopy; circular dichroism; ATPase activity assays; site-directed mutagenesis (D834E)\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal structural and biochemical methods plus mutagenesis in one study\",\n      \"pmids\": [\"18311911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dominant missense mutations in ABCC9 causing Cantú syndrome reduce ATP-mediated inhibition of the KATP channel, resulting in channel opening (gain-of-function). All mutations altered amino acids in or close to the transmembrane domains of SUR2.\",\n      \"method\": \"Family-based exome sequencing; electrophysiological measurements of mutant channels\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — electrophysiology confirmed in 14/16 individuals; replicated by independent group (PMID:22608503)\",\n      \"pmids\": [\"22610116\", \"22608503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Cantú syndrome mutations in ABCC9 are missense and affect a mutation hotspot at Arg1154 within the second type 1 transmembrane region of SUR2, consistent with an activating (gain-of-function) mechanism for the KATP channel.\",\n      \"method\": \"Exome sequencing of proband-parent trios and unrelated cases; Sanger sequencing validation\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Strong — sequencing only without direct functional assay in this paper, but independently replicated\",\n      \"pmids\": [\"22608503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CpG methylation of the ABCC9 (SUR2) promoter regulates its expression in cardiomyocytes. Bisulfite sequencing showed 57.6% CpG methylation in the SUR2 promoter in HL-1 cells (vs. 0.14% for SUR1), and treatment with 5-aza-2'-deoxycytidine increased both unmethylated CpG fraction and SUR2 mRNA expression.\",\n      \"method\": \"Bisulfite sequencing of genomic DNA; 5-aza-2'-deoxycytidine treatment; quantitative mRNA expression analysis in HL-1 cardiomyocytes\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal methods (bisulfite sequencing + pharmacological demethylation) in single lab; caveats acknowledged about non-methylation effects of Aza-dC\",\n      \"pmids\": [\"22844491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The V734I mutation in ABCC9 (SUR2B) reduces sensitivity of Kir6.2/SUR2B channels to MgATP inhibition and reduces MgNDP (MgADP, MgGDP, MgUDP) activation, specifically in vascular (Kir6.2/SUR2B) but not cardiac (Kir6.2/SUR2A) or Kir6.1/SUR2B channel combinations, implicating impaired vascular KATP channel response to intracellular nucleotides in susceptibility to coronary spasm and myocardial infarction.\",\n      \"method\": \"Patch-clamp electrophysiology (inside-out patches) of mutant channels coexpressed in Xenopus oocytes or HEK cells; splice variant-specific analysis of SUR2A vs SUR2B\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous inside-out patch-clamp with multiple nucleotide conditions and multiple channel subunit combinations, single lab\",\n      \"pmids\": [\"23739550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ABCC9 mutations (V734I and S1402C) cause gain-of-function of IK-ATP: V734I yielded a Mg-ATP IC50 5-fold that of wild-type; S1402C shifted ATP IC50 from 8.5 ± 2 mM to 13.4 ± 5 µM. These gain-of-function variants are associated with Brugada and early repolarization syndromes.\",\n      \"method\": \"Whole-cell and inside-out patch-clamp of mutant channels expressed in TSA201 cells; direct sequencing\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous electrophysiology but single lab; small patient cohort\",\n      \"pmids\": [\"24439875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Abcc9 is required for the neonatal heart's transition from glycolytic to oxidative (mitochondrial) metabolism. Abcc9 knockout (exon 5 deletion) cardiomyocytes showed mitochondria unresponsive to the KATP agonist diazoxide, rapid mitochondrial membrane potential collapse under oxidative stress, reduced fatty acid oxidation, reduced oxygen consumption, and morphologically immature mitochondria with reduced cross-sectional area and intermitochondrial contacts.\",\n      \"method\": \"Mouse knockout model (exon 5 deletion); mitochondrial membrane potential assays; diazoxide stimulation; fatty acid oxidation assays; oxygen consumption measurements; electron microscopy\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional readouts in KO mouse model; single lab\",\n      \"pmids\": [\"24648545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Three Cantú syndrome ABCC9 mutations (P432L/P429L, A478V/A475V, C1043Y/C1039Y in human/rat SUR2A) all cause gain-of-function via at least two distinct mechanisms: P429L and A475V mutations enhance MgADP activation without altering ATP inhibition sensitivity; C1039Y mutation decreases ATP inhibition sensitivity and glibenclamide sensitivity without altering MgADP activation.\",\n      \"method\": \"Macroscopic 86Rb+ efflux assays; inside-out patch-clamp electrophysiology measuring ATP inhibition and MgADP activation; channels coexpressed with Kir6.2 in Xenopus oocytes\",\n      \"journal\": \"The Journal of general physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — two orthogonal functional assays (Rb+ efflux + patch-clamp) with multiple mutants, single lab\",\n      \"pmids\": [\"26621776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous splice-site mutation in ABCC9 (c.1320+1 G>A) causes in-frame deletion of exon 8, resulting in non-functional SUR2-containing KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice and reduced activity, cardiac dysfunction, and ventricular enlargement in zebrafish, defining the ABCC9-related Intellectual disability Myopathy Syndrome (AIMS).\",\n      \"method\": \"Recombinant channel expression and functional assays; mouse phenotyping; zebrafish phenotyping; patient exome sequencing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant functional assay plus two animal model phenotyping studies, single coordinated study\",\n      \"pmids\": [\"31575858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Four rare ABCC9 missense variants (A355S, M941V, H1305Y, K1379Q) identified in sudden unexpected natural death cases all produce gain-of-function phenotypes when expressed as SUR2A with Kir6.2 in HEK-293 cells: A355S and M941V increase overall patch current; M941V, H1305Y, and K1379Q reduce sensitivity to inhibitory cytosolic ATP. None altered unitary channel current or surface expression (biotinylation assays), indicating enhanced open-state probability.\",\n      \"method\": \"Patch-clamp electrophysiology; surface biotinylation assays in HEK-293 cells expressing human SUR2A + Kir6.2\",\n      \"journal\": \"Forensic science international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous patch-clamp plus biochemical assay but single lab, no replication\",\n      \"pmids\": [\"30878466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KCNJ8/ABCC9-containing KATP channel cell-autonomously regulates brain vascular smooth muscle cell (VSMC) differentiation through modulation of intracellular Ca2+ oscillation via voltage-dependent calcium channels. Genetic/chemical inhibition or activation of KATP channel function leads to brain-selective suppression or promotion of arterial/arteriolar VSMC differentiation. Kcnj8 knockout mice showed deficiency in vasoconstrictive capacity and impaired neuronal-evoked vasodilation.\",\n      \"method\": \"Mouse knockout; zebrafish genetic models; cell culture; pharmacological KATP channel inhibition/activation; intracellular Ca2+ imaging; neurovascular coupling measurements\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model organisms (mouse, zebrafish, cell culture) with pharmacological and genetic manipulation plus mechanistic Ca2+ imaging\",\n      \"pmids\": [\"35588738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A heterozygous ABCC9 in-frame deletion variant (indel1055; p.Leu1055_Glu1058delinsPro) in SUR2A causes gain-of-function with increased IC50 for ATP inhibition, as demonstrated by inside-out patch-clamp of channels formed by Kir6.2 and mutant SUR2A in Cosm6 cells. A second variant p.Ile416Thr did not differ functionally from wild-type.\",\n      \"method\": \"Inside-out patch-clamp electrophysiology of mutant SUR2A + Kir6.2 in Cosm6 cells\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous patch-clamp but single variant in single lab, no replication\",\n      \"pmids\": [\"36336713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A novel heterozygous ABCC9 variant (p.Gly814Trp) in SUR2B causes gain-of-function KATP channel activity: cells expressing hKir6.1/hSUR2B-Gly814Trp showed hyperpolarized membrane potential, and inside-out patch-clamp demonstrated decreased sensitivity to ATP inhibition. The location of this variant in the signature motif of NBD1 reveals an unrecognized functional role of the first glycine in the ABC protein NBD signature motif.\",\n      \"method\": \"Stable cell expression of hKir6.1 + hSUR2B mutant; membrane potential measurements; inside-out patch-clamp electrophysiology\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — patch-clamp with membrane potential readout, single lab, single variant\",\n      \"pmids\": [\"39031464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABCC9 knockdown in isoproterenol-treated AC16 cardiomyocytes attenuates myocardial hypertrophy and reduces cardiomyocyte apoptosis and oxidative stress by inhibiting the PI3K/AKT signaling pathway and improving mitochondrial membrane potential. The protective effects were abolished by PI3K/AKT activator 740Y-P, placing ABCC9 upstream of PI3K/AKT in this pathway.\",\n      \"method\": \"siRNA knockdown in AC16 cardiomyocytes; western blot for PI3K/AKT pathway components; mitochondrial membrane potential assay; flow cytometry for ROS and apoptosis; pharmacological rescue with 740Y-P\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — epistasis via pharmacological rescue plus multiple readouts, single lab, no replication\",\n      \"pmids\": [\"41347799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TRIM11 promotes ABCC9 expression in nasopharyngeal carcinoma by ubiquitin-mediated (p62-selective autophagic) degradation of Daple, which upregulates β-catenin, which directly binds the ABCC9 promoter to induce its transcription, thereby enhancing multidrug resistance.\",\n      \"method\": \"qRT-PCR; Co-IP; ubiquitination assays; promoter binding assays; in vitro and in vivo cisplatin resistance models\",\n      \"journal\": \"Oncogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — multiple mechanistic assays (Co-IP, promoter binding, in vivo) but single lab; ABCC9 is downstream effector in this pathway\",\n      \"pmids\": [\"32382014\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABCC9 encodes SUR2, the regulatory subunit of heterooctameric KATP channels (with Kir6.x pore-forming subunits); SUR2 harbors ATPase activity in its asymmetric NBD1/NBD2 domains whose heterodomain interaction optimizes catalytic output, and catalytically driven conformational changes gate the Kir6 channel pore—gain-of-function mutations (reducing ATP inhibition or enhancing MgADP activation) cause Cantú syndrome and arrhythmia susceptibility, while loss-of-function mutations cause dilated cardiomyopathy, intellectual disability/myopathy syndrome (AIMS), and neonatal metabolic failure; the KATP channel additionally regulates brain VSMC differentiation via Ca2+ oscillation, and ABCC9 expression is regulated at the transcriptional level by CpG methylation and by the TRIM11/Daple/β-catenin axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABCC9 encodes SUR2, the regulatory subunit that assembles with Kir6.x pore-forming subunits to form ATP-sensitive potassium (KATP) channels coupling cellular metabolic state to membrane excitability [#0, #2]. SUR2 harbors intrinsic ATPase activity concentrated in NBD2 and, to a lesser degree, NBD1, whose heterodomain NBD1/NBD2 interaction drives conformational rearrangements that potentiate catalysis and translate nucleotide binding into pore regulation [#1]. This catalytic cycle decodes intracellular nucleotide signals: ATP binding inhibits the channel while MgADP/MgNDP binding activates it, and disease mutations distort this balance through at least two distinct routes—reduced ATP inhibition or enhanced MgADP activation—both yielding gain-of-function channel opening [#5, #8, #12]. Gain-of-function ABCC9 variants cause Cantú syndrome [#2, #3] and confer susceptibility to arrhythmia, Brugada/early repolarization, and sudden death [#6, #10], whereas loss-of-function from a homozygous splice variant defines ABCC9-related Intellectual disability Myopathy Syndrome (AIMS) with cardiac dysfunction in mouse and zebrafish models [#9]. Beyond excitability, ABCC9 is required for the neonatal cardiac transition to oxidative mitochondrial metabolism [#7], and the KCNJ8/ABCC9 channel cell-autonomously regulates brain vascular smooth muscle differentiation through Ca2+ oscillation [#11]. ABCC9 transcription is controlled by CpG methylation of its promoter [#4] and by a TRIM11/Daple/β-catenin axis that drives multidrug resistance in nasopharyngeal carcinoma [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that ABCC9 disease mutations cluster near the SUR2A catalytic ATPase pocket and act by distorting the intrinsic ATP hydrolytic cycle, defining defective catalysis-mediated pore regulation as a disease mechanism.\",\n      \"evidence\": \"Genomic DNA scanning plus ATPase and electrophysiology assays of mutant SUR2A\",\n      \"pmids\": [\"15034580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of how catalysis gates the Kir6 pore\", \"Specific clinical phenotype-mutation correlations not yet established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Localized SUR2A ATPase activity to the nucleotide-binding domains and showed the asymmetric NBD1/NBD2 heterodomain interaction potentiates catalysis, explaining how nucleotide sensing is mechanically organized.\",\n      \"evidence\": \"Purified recombinant NBD1/NBD2 domains analyzed by AFM, TEM, circular dichroism, ATPase assays and D834E mutagenesis\",\n      \"pmids\": [\"18311911\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Domain studies done in isolation, not in intact assembled channel\", \"Link from NBD conformational change to pore gating inferred, not directly visualized\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified ABCC9 gain-of-function mutations reducing ATP inhibition as the cause of Cantú syndrome, establishing a human disease driven by excess KATP channel opening.\",\n      \"evidence\": \"Family-based and trio exome sequencing with electrophysiology of mutant channels; independent replication\",\n      \"pmids\": [\"22610116\", \"22608503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions of different SUR2 splice variants not resolved\", \"Mechanism by which transmembrane-domain mutations alter ATP sensitivity not structurally defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated splice-variant- and tissue-specificity of ABCC9 channel dysfunction, showing the V734I variant selectively impairs vascular (SUR2B) nucleotide responses linked to coronary spasm.\",\n      \"evidence\": \"Inside-out patch-clamp of mutant channels across SUR2A/SUR2B/Kir6.x combinations in oocytes and HEK cells\",\n      \"pmids\": [\"23739550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo vascular phenotype of the variant not tested\", \"Did not address why the same variant is benign in cardiac channels mechanistically\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Broadened the arrhythmia spectrum by showing ABCC9 gain-of-function variants underlie Brugada and early repolarization syndromes via increased IK-ATP.\",\n      \"evidence\": \"Whole-cell and inside-out patch-clamp of mutant channels in TSA201 cells with sequencing\",\n      \"pmids\": [\"24439875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, small patient cohort\", \"Causality at the organismal/clinical level not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed a metabolic role beyond excitability, showing Abcc9 is required for the neonatal heart's switch from glycolytic to oxidative mitochondrial metabolism.\",\n      \"evidence\": \"Abcc9 knockout mouse with mitochondrial membrane potential, fatty acid oxidation, oxygen consumption assays, diazoxide stimulation and electron microscopy\",\n      \"pmids\": [\"24648545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between sarcolemmal KATP channel function and mitochondrial maturation unresolved\", \"Whether the effect is channel-dependent or independent not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved that Cantú gain-of-function arises through at least two mechanistically distinct routes—enhanced MgADP activation versus decreased ATP inhibition—clarifying the molecular heterogeneity of a single syndrome.\",\n      \"evidence\": \"86Rb+ efflux and inside-out patch-clamp of multiple Cantú mutants coexpressed with Kir6.2 in oocytes\",\n      \"pmids\": [\"26621776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the two mechanisms produce distinct clinical severity not addressed\", \"Structural correlates of each mechanism not defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the loss-of-function end of the ABCC9 spectrum, showing a splice variant producing non-functional channels causes the AIMS syndrome with conserved phenotypes across species.\",\n      \"evidence\": \"Recombinant channel assays plus mouse and zebrafish phenotyping with patient exome sequencing\",\n      \"pmids\": [\"31575858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking SUR2 loss to intellectual disability/myopathy not detailed\", \"Cell types driving each phenotypic feature not isolated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected rare ABCC9 variants to sudden unexpected death by showing they enhance open-state probability without altering unitary current or surface expression.\",\n      \"evidence\": \"Patch-clamp and surface biotinylation of human SUR2A + Kir6.2 in HEK-293 cells\",\n      \"pmids\": [\"30878466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no replication\", \"Direct causal contribution to death events not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a developmental role in which the KCNJ8/ABCC9 channel cell-autonomously controls brain vascular smooth muscle differentiation via Ca2+ oscillation, linking the channel to neurovascular coupling.\",\n      \"evidence\": \"Mouse and zebrafish genetics, cell culture, pharmacology, Ca2+ imaging and neurovascular coupling measurements\",\n      \"pmids\": [\"35588738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why this regulation is brain-selective not fully explained\", \"Connection to Cantú vascular phenotypes not directly tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Added an in-frame deletion gain-of-function variant with increased ATP IC50, extending the catalogue of ATP-inhibition-impairing mutations.\",\n      \"evidence\": \"Inside-out patch-clamp of mutant SUR2A + Kir6.2 in Cosm6 cells\",\n      \"pmids\": [\"36336713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant, single lab, no replication\", \"Clinical phenotype not functionally tied to the variant\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Assigned a functional role to the first glycine of the ABC NBD signature motif by showing a SUR2B variant there causes gain-of-function with reduced ATP sensitivity.\",\n      \"evidence\": \"Stable hKir6.1 + hSUR2B mutant expression with membrane potential and inside-out patch-clamp\",\n      \"pmids\": [\"39031464\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single variant, single lab\", \"Structural mechanism by which the signature-motif glycine controls ATP gating not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ABCC9 upstream of PI3K/AKT signaling in cardiomyocyte hypertrophy, showing knockdown reduces apoptosis and oxidative stress dependent on this pathway.\",\n      \"evidence\": \"siRNA knockdown in AC16 cardiomyocytes with western blot, mitochondrial and ROS/apoptosis assays and pharmacological rescue with 740Y-P\",\n      \"pmids\": [\"41347799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no replication\", \"Whether the effect requires channel activity versus a non-channel role unclear\", \"In vivo relevance not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a transcriptional regulatory axis in which TRIM11/Daple/β-catenin drives ABCC9 expression to confer multidrug resistance in nasopharyngeal carcinoma.\",\n      \"evidence\": \"qRT-PCR, Co-IP, ubiquitination and promoter binding assays with in vitro and in vivo cisplatin resistance models\",\n      \"pmids\": [\"32382014\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ABCC9 as downstream effector; direct drug-efflux role not demonstrated here\", \"Single lab; generality across cancers not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How catalytically driven NBD conformational changes are mechanically transmitted to gate the Kir6 pore in the assembled channel, and how the same molecule's metabolic and developmental roles relate to its channel function, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of mutation-to-gating coupling in intact octamer\", \"Channel-dependent vs channel-independent contributions to metabolic/developmental phenotypes undissected\", \"Tissue-specific splice-variant roles incompletely mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 5]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [2, 5, 8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 9, 15]}\n    ],\n    \"complexes\": [\"KATP channel (SUR2/Kir6.x)\"],\n    \"partners\": [\"KCNJ8\", \"Kir6.2\", \"Kir6.1\", \"TRIM11\", \"Daple\", \"CTNNB1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}